Françoise Brucker-Davis

Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.

BACKGROUND To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy. METHODS One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined. RESULTS Sixty-two of the 127 patients had positive whole-body radioiodine scans by one or both techniques. The scans obtained after stimulation with thyrotropin were equivalent to the scans obtained after withdrawal of thyroid hormone in 41 of these patients (66 percent), superior in 3 (5 percent), and inferior in 18 (29 percent). When the 65 patients with concordant negative scans were included, the two scans were equivalent in 106 patients (83 percent). Eight patients (13 percent of those with at least one positive scan) were treated with radioiodine on the basis of superior scans done after withdrawal of thyroid hormone. Serum thyroglobulin concentrations increased in 15 of 35 tested patients: 14 after withdrawal of thyroid hormone and 13 after administration of thyrotropin. Patients had more symptoms of hypothyroidism (P<0.001) and dysphoric mood states (P<0.001) after withdrawal of thyroid hormone than after administration of thyrotropin. CONCLUSIONS Thyrotropin stimulates radioiodine uptake for scanning in patients with thyroid cancer, but the sensitivity of scanning after the administration of thyrotropin is less than that after the withdrawal of thyroid hormone. Thyrotropin scanning is associated with fewer symptoms and dysphoric mood states.

Genetic and Clinical Features of 42 Kindreds with Resistance to Thyroid Hormone: The National Institutes of Health Prospective Study

Resistance to thyroid hormone, first described by Refetoff and coworkers in 1967 [1], is characterized by decreased pituitary and tissue responsiveness to thyroid hormone. Patients typically have elevated serum free and total triiodothyronine (T3) and thyroxine (T4) levels and inappropriately normal or elevated thyroid-stimulating hormone (TSH) levels. The phenotype is heterogeneous; classic features include attention-deficit hyperactivity disorder, growth delay, and tachycardia [2, 3]. Resistance to thyroid hormone is usually transmitted in an autosomal dominant manner, but sporadic de novo cases are common, and recessive inheritance is rare [1, 4]. Linkage between resistance to thyroid hormone and the thyroid hormone receptor (TR ) gene was shown in 1988 [5]. Since then, about 100 mutations have been found in that gene [6], clustered primarily in two hot spots in the T3-binding domain (exons 9 and 10), respecting the integrity of the dimerization domain [7]. Mutant receptors have normal DNA binding, but T3 binding and transactivation are impaired to varying degrees [8, 9]. Moreover, the abnormal receptors antagonize the function of normal receptors in a dominant negative manner [10, 11]. Thyroid hormone action is mediated through two types of nuclear receptors, (TR ) and TR [12, 13], which have different organ distributions. Thus, resistance to thyroid hormone provides an exciting opportunity to study the in vivo, tissue-specific action of thyroid hormone. The prevalence of resistance to thyroid hormone is unknown but is thought to be low. The phenotype is heterogeneous and ranges from highly symptomatic to subclinical [2, 3, 14]. Resistance to thyroid hormone is traditionally defined as generalized resistance and, more rarely, as pituitary resistance [15]. In generalized resistance, pituitary and peripheral tissues are not always involved to the same degree, and this creates a mosaic of hypothyroid and hyperthyroid symptoms in the patient. If the degree of resistance is similar in pituitary and peripheral tissues, high levels of thyroid hormone result in compensation, and patients are euthyroid. Patients with pituitary resistance are predominantly hyperthyroid and have hypermetabolism and tachycardia [16]. A single case of isolated peripheral resistance has been reported [17]. Since 1976, 104 patients with resistance to thyroid hormone from 42 unrelated kindreds have been studied prospectively at the National Institutes of Health (NIH), along with 114 of their unaffected relatives, who serve as a control group with environmental and genetic back-grounds similar to those of the patients. Here, we report the results of their initial evaluation. Our goals were to analyze the resistance-to-thyroid-hormone phenotype, including its newly recognized features; to assess the organ specificity of resistance to thyroid hormone; and to define factors contributing to the heterogeneity of the phenotype. Methods Patients and Controls Data collected at the time of initial hospitalization at the NIH were analyzed for 218 persons (104 with and 114 without resistance to thyroid hormone, including 29 persons who had married into families that had resistance to thyroid hormone) from 42 unrelated families. Patients were referred to the NIH for the evaluation of inappropriate TSH secretion. Appropriate informed consent was obtained as approved by the National Institute of Diabetes and Digestive and Kidney Diseases institutional review board. Participants younger than 16 years of age were considered to be children. A full personal and family history was taken from each participant, and specific information about goiter; cardiac symptoms; speech; ear, nose, and throat infections; and hearing problems was collected through interviews. Resting pulse (taken while participants were sleeping or after at least 10 minutes of rest) and goiter were recorded from physical examination, and height (an average of 10 measurements with a stadiometer), weight, and weight-for-height were plotted using charts adapted from Hamill and colleagues [18]. Diagnostic Criteria Resistance to thyroid hormone was diagnosed on the basis of elevated free and total thyroid hormone levels in the presence of normal or elevated TSH levels. Blood was analyzed for levels of T3 (Quanticoat TM, Kallesad Diagnostic, Chasco, Minnesota), T4 (fluorescein polarization immunoassay, Abbott TDx, Abbott Park, Illinois), free T4 (Gammacoat TM two-step RIA, INC-STAR, Stillwater, Minnesota), free T3 (RIA, Becton Dickinson kit, SmithKline Beecham Laboratories, Van Nuys, California), TSH (MAIAclone, Serono Diagnostics, Walpole, Massachusetts), -subunit of TSH (RIA, Hazelton-Washington, Vienna, Virginia), prolactin (TOSOH AIA-1200, Hazelton), and thyroxine-binding globulin (TBG) (Cornings Immunophase, TBG125 I, Corning Medical, Norwood, Massachusetts). Thyroid uptake of 123I was measured at 24 hours. Diagnosis was confirmed by DNA analysis using traditional methods in 14 families [7] or using a new strategy, a modification of single-stranded conformational polymorphism, to screen [19] and identify the other mutations [20]. We used the new consensus [6] for exon, codon, and nucleotide designation. Parents of affected persons were screened if possible; if both parents tested negative, patients were considered to have sporadic cases. Magnetic resonance imaging (MRI) of the pituitary gland was done to rule out a TSH-secreting pituitary adenoma. Parameters of Thyroid Hormone Action Assessment of Pituitary Resistance In patients with no history of thyroidectomy who were not receiving thyroid medication (untreated patients), TSH-releasing hormone tests (Relefact, Ferring Laboratory, Suffern, New York) were done. Levels of TSH, -subunit of TSH, and prolactin were measured 0 and 30 minutes after intravenous injection of 500 g (for adults) or 7 g/kg body weight (for children) of TSH-releasing hormone. Assessment of Peripheral Resistance Attention-deficit hyperactivity disorder and IQ were assessed using previously described methods [21, 22]. Briefly, a neuropsychologist, blinded to the diagnosis of resistance to thyroid hormone assessed IQ by using age-appropriate Wechsler intelligence tests. Attention-deficit hyperactivity disorder was diagnosed by psychiatrists, also blinded to the diagnosis of resistance to thyroid hormone, using appropriate structured psychiatric interviews. Right-ankle reflex was measured with an achillometer (Polymed GmbH, Polymed Medical Center, Medizintechnik, Glattbugg ZH, Switzerland) connected to a 1511B electrocardiograph (Hewlett-Packard, Waltram, Massachusetts) in untreated persons. Results given are each an average of three measurements. Audiologic evaluation included threshold tests of pure tones and speech stimuli and biochemical studies of middle-ear function (tympanometry and acoustic reflexes). Significant hearing loss was defined as a speech threshold greater than 20 decibels. Bone age was determined in children by using a hand-wrist radiograph according to the method of Greulich and Pyle [23]. Standard deviations were calculated using the Brush foundation table [23]. Basal metabolic rate was measured at Georgetown University Hospital in Washington, D.C., in untreated persons by using a Sensor Medics 2900 metabolic cart (Sensor Medics Corp., Yorba Linda, California). Results are expressed as a ratio between observed and theoretical basal metabolic rate adjusted for age, sex, height, and weight. Pulsed and continuous echocardiography assessed cardiac dimension and cardiac cycle intervals in 36 untreated adults with resistance to thyroid hormone and 15 untreated adults without resistance. Indices of thyroid hormone actionlevels of cholesterol, ferritin (Abbott Diagnostics), testosterone-binding globulin (TeBG) (Hazelton, Washington, Virginia), and carotene (SmithKline Beecham Clinical Laboratories)were measured [24-27] in fasting, untreated patients. Levels of IgG, IgA, and IgM were also measured. Criteria for Organ Assessment of Thyroid Hormone Action Table 1 shows the variables that were selected to assess end-organ action of thyroid hormone, and it defines the hypothyroid, euthyroid, and hyperthyroid ranges. For basal metabolic rate and for cholesterol, ferritin, and TeBG levels, normal ranges were those validated at our center; for resting pulse, normal values were adapted from Cole [28]; for bone and brain, ranges were based on clinical observation in persons with congenital hypothyroidism. Table 1. Criteria for Tissue Assessment of Thyroid Hormone Action Statistical Analysis Continuous variables are expressed as mean SE, and binary variables are expressed as proportion SE. We estimated SE for all variables (continuous and binary) using a bootstrap approach [29] by resampling the 42 families (not the individual persons) with replacement 1000 times and estimating the distribution of means or proportions from the 1000 replicates. Specifically, we estimated the mean (or proportion) in each replicate and estimated the SE from the sample of 1000 means (or proportions). This procedure allowed us to take into account correlations among persons within families, because we used families rather than individual persons as resampling units. Similarly, we did statistical tests that took correlations within families into account and yielded P values that discriminated between the factor being studied [such as whether a person had resistance to thyroid hormone] and familial traits. We did four sets of statistical tests that compared 1) persons who had resistance to thyroid hormone with persons who did not; 2) persons with resistance to thyroid hormone who had exon 9 mutations with persons with resistance to thyroid hormone who had exon 10 mutations; 3) persons with resistance to thyroid hormone who had an affected mother with persons with resistance who did not have an affected mother, separately in children and in adults; and 4) children with adults, separately acco

Thyroid hormones correlate with symptoms of hyperactivity but not inattention in attention deficit hyperactivity disorder

The diagnostic validity of dividing attention deficit hyperactivity disorder (ADHD) into two distinct subgroups, one with and one without hyperactivity, is controversial since there have been no physiological differences demonstrated between these two subgroups. In this study, the relationship between thyroid hormones and symptoms of hyperactivity was examined in subjects with resistance to thyroid hormone (RTH) and their unaffected family members. Clinical data were collected on 152 subjects; 75 subjects with RTH and 77 family members without RTH. Each subject was assessed using DSM-III-R criterion based, structured psychiatric interviews, and Total T3 (TT3), Total T4 (TT4) and TSH concentrations were measured. The total number of ADHD symptoms were assigned to either inattention or hyperactivity subgroups using DSM-III-R criteria. The total number of ADHD symptoms were then reassigned to inattention or hyperactivity/impulsivity subgroups using DSM-IV criteria. Pearson R correlation coefficients were calculated separately for the RTH and unaffected family members groups in order to determine the relationships between TSH, TT3 and TT4 concentrations, and the DSM-III-R and DSM-IV symptom categories of ADHD in both groups. TSH concentrations were not significantly correlated with any of the symptom categories in either group. However, in the RTH group, both TT3 and TT4 concentrations were significantly and positively correlated with total symptoms of ADHD (DSM-III-R) as well as symptoms of inattention (DSM-III-R) and symptoms of hyperactivity (DSM-III-R). When DSM-IV criteria were used, which reassigns symptoms of impulsivity from the inattention to the hyperactivity category, only the positive correlation between TT3 and TT4 concentrations and symptoms of hyperactivity/impulsivity (DSM-IV) remained significant. In the group of unaffected family members, the relationship between TT3 concentrations and symptoms of hyperactivity/impulsivity (DSM-IV) was the only significant correlation. The data support the hypothesis that thyroid hormones may provide a physiological basis for the dichotomy between symptoms of inattention and symptoms of hyperactivity, particularly when DSM-IV criteria are applied.

Cord Blood Thyroid Tests in Boys Born With and Without Cryptorchidism: Correlations with Birth Parameters and In Utero Xenobiotics Exposure

BACKGROUND In utero exposure to environmental chemicals can result in reproductive toxicity via endocrine disruption mechanisms. Whether some of those contaminants also have an impact on fetal thyroid function or pathways, and, thus, potentially on neuropsychological development, is still debated. METHODS We used samples from a cord blood (CB) and milk bank, established for a research on cryptorchidism and xenobiotic exposure to compounds known for their anti-androgenic and/or estrogenic activity, to study CB thyroid tests and their correlation with CB and milk xenobiotics concentrations in boys born in Nice area. RESULTS No difference was found in thyroid tests between 60 cryptorchid boys and 76 matched controls (median thyroid stimulating hormone 5.97 vs. 6.55 mUI/L, free thyroxine [fT4] 13.1 vs. 12.9 pmol/L, free triiodothyronine [fT3] 1.9 vs. 2.1 pmol/L), with no influence of season of birth, gestational age, maternal smoking, or mode of delivery (except for higher fT4 in control boys born vaginally). FT4 was correlated with fetal growth only in cryptorchid boys. Since we had previously shown differences between cryptorchid and controls exposure, we studied correlations of thyroid tests with xenobiotics in control boys only. All tested CB or maternal milk was contaminated by one or more selected xenobiotics, mainly polychlorinated biphenyls (PCBs), dichloro diphenyl dichloroethylène (DDE), dibutylphthalate, hexachlorobenzene, and bisphenol A. We found a significant negative correlation between fT4 and concentrations of PCB118, PC180, and DDE in milk (respectively r = -0.342, p < 0.03, r = -0.296, p = 0.031, r = -0.315, p = 0.016), persisting after adjustment for mode of delivery. There was a significant positive correlation of fT3 with milk concentrations of PCB138, PCB153, ΣPCB, and dibutylphthalate (respectively r = 0.31, p = 0.016, r = 0.28, p = 0.029; r = 0.34, p = 0.0079 and r = 0.272, p = 0.0295), with a trend for PCB180 (r = 0.259, p = 0.061). There was no correlation of thyroid stimulating hormone with any of the measured xenobiotics, except for a weak negative trend with CB bisphenol A (r = -0.25, p = 0.077). CONCLUSIONS CB thyroid tests are within normal range in cryptorchid boys, similar to controls. Our data in controls suggest a possible weak correlation between in utero exposure to some xenobiotics (PCBs, DDE) and fT3 and fT4 CB concentrations, with usually negative correlations with fT4 and positive with fT3 concentrations, which we speculate could suggest an impact on deiodinases.

Cord blood Insulin‐like peptide 3 (INSL3) but not testosterone is reduced in idiopathic cryptorchidism

Cryptorchidism, the most frequent congenital malformation in full‐term male newborns, increases the risk of hypofertility and testicular cancer. Most cases remain idiopathic but epidemiological and experimental studies have suggested a role of both genetic and environmental factors. Physiological testicular descent is regulated by two major Leydig hormones: insulin‐like peptide 3 (INSL3) and testosterone.

Relative Impact of Iodine Supplementation and Maternal Smoking on Cord Blood Thyroglobulin in Pregnant Women with Normal Thyroid Function

Objective: To assess the impact on cord blood (CB) thyroglobulin (Tg) of early iodine supplementation during pregnancy. Methods: A total of 111 healthy pregnant women with normal thyroid function were included in a prospective randomized study and divided into two groups with (150 µg/day) or without iodine supplementation started during the first trimester. Maternal smoking was assessed qualitatively by self-reported statements and quantitatively by cotininuria. Exhaustive thyroid tests were performed at delivery in the mother and in CB. Results: Third-trimester ioduria documented compliance with iodine supplementation (160 vs. 76 µg/l in controls). CB Tg was not different between the iodine and control groups (median 77 vs. 79.5 ng/ml, respectively) and did not correlate with maternal ioduria. CB Tg was higher in newborns from smoking mothers (114 vs. 64.7 ng/ml) and correlated with self-reported smoking status more than with maternal cotininuria. Nonsmokers had no difference in CB Tg whether they took iodine supplementation or not, as opposed to smokers, who tended to benefit from supplementation. Conclusions: Iodine supplementation does not significantly impact CB Tg in healthy nonsmoker pregnant women selected for normal thyroid function, as opposed to maternal smoking. CB Tg appears to be a marker of in utero tobacco exposure. In areas of mild iodine deficiency, iodine supplementation could especially benefit the fetuses of smokers.

Effectiveness of Long-Acting Octreotide in Suppressing Hormonogenesis and Tumor Growth in Thyrotropin-Secreting Pituitary Adenomas: Report of Two Cases

AbstractBackground. The subcutaneous (s.c.) administration of somatostatin analogs, such as octreotide acetate (SMS) and lanreotide, in patients with thyrotropin (TSH)-secreting pituitary adenomas (TSPAs)—thyrotropinomas with residual tumor after initial surgical therapy is effective in controlling hyperthyroidism, as well as curtailing tumor growth in the majority of patients. Long-acting preparations of the above agents, i.e. SMS-LAR and lanreotide-SR, have been synthesized and can be administered as depot injections intramuscularly (i.m.) at intervals of several weeks. Recent studies have reported on preliminary data regarding the use of such preparations in patients with TSPAs. Materials and Methods: We present two cases of TSPAs with residual tumor following transsphenoidal adenomectomy. Neither of the two patients underwent external beam pituitary irradiation. The presence and extent of tumoral TSH hypersecretion was assessed by standard biochemical and dynamic endocrine testing, while tumor size was evaluated by conventional radiographic techniques. Results: In both patients, TSH secretion was effectively suppressed by SMS-LAR. Moreover, administration of this compound halted further tumor growth, as well as resulted in improved patient comfort, for 12 and 10 months respectively. Conclusion: Our date corroborate earlier reports on the usefulness of SMS-LAR in the medical management of patients with TSPAs who have residual disease after initial pituitary surgery and/or irradiation.

Severe hyperemesis gravidarum associated with gestational thyrotoxicosis and acute biliary pancreatitis

[1] Spellacy WN, Gravem H, Fisch RO. The umbilical cord complications of true knots, nuchal coils, and cords around the body. Report from the collaborative study of cerebral palsy. Am J Obstet Gynecol 1966;94:1136–42. [2] Ramón Y, Cajal CL, Martı́nez RO. Prenatal diagnosis of true knot of the umbilical cord. Ultrasound Obstet Gynecol 2004;23:99–100. [3] Hershkovitz R, Silberstein T, Sheiner E, et al. Risk factors associated with true knot of the umbilical cord. Eur J Obstet Gynecol Reprod Biol 2001;98:36–9. [4] Sørnes T. Umbilical cord knots. Acta Obstet Gynecol Scand 2000;79:157–9. pregnancy, suggestive of HG. She had a history of severe HG (32% weight loss) with gestational hyperthyroidism during her previous pregnancy 4 years earlier, which required transient propylthiouracyl (PTU) treatment until 21 WA. She had no other risk factor of HG. Graves’ disease, which is the main differential diagnosis of hyperthyroidism, was ruled out, as anti-TSH-receptor and antiTPO antibodies were negative. She was started on intravenous rehydration associated with food withdrawal and use of antivomiting drugs. However, as hyperthyroidism increased markedly (Table 1) with a worsening of weight loss ( 13 kg; 21% of body weight), we decided to introduce PTU treatment. Due to an

Contents Vol. 1, 2012

Maria Alevizaki, Athens Ana Aranda, Madrid Rebecca Bahn, Rochester, Minn. Paul Banga, London Luigi Bartalena, Varese Bernadette Biondi, Naples Anita Boelen, Amsterdam Georg Brabant, Lubeck Henning Dralle, Halle Murat Erdogan, Ankara Creswell J. Eastman, Westmead, N.S.W. Valentin Fadeyev, Moscow Ulla Feldt-Rasmussen, Copenhagen Laszlo Hegedus, Odense George J. Kahaly, Mainz Rui Maciel, São Paolo Ana Luiza Maia, Porto Alegre Jens Mittag, Stockholm Ralf Paschke, Leipzig Simon Pearce, Newcastle-upon-Tyne Robin Peeters, Rotterdam Kris Poppe, Bruxelles Samuel Refetoff , Chicago, Ill. Jacques Samarut, Lyon Pilar Santisteban, Madrid YoungKee Shong, Seoul Jan Smit, Leiden Mark Vanderpump, London Th eo Visser, Rotterdam Paolo Vitti, Pisa Graham Williams, London Shunichi Yamashita, Nagasaki Mariastella Zannini, Naples Luca Persani, Milan (Translational Th yroidology)